1. Technical Field
The invention relates to production of an 18F radioisotope by means of proton irradiation of 18O enriched water.
2. Background
The 18F isotope (hereinafter, F-18 isotope or F-18) has become widely used in nuclear medicine for diagnostic studies using a Positron Emission Tomography (PET) body scanning technique. The F-18 is typically used to label an injectable glucose derivative. Because of its short half-life (109 min), this isotope must be used as soon as possible after production. This makes it impossible to accumulate a sufficient quantity for delayed use. Therefore, work shifts usually start near midnight with production for distant (via automobile) hospitals first, followed by that for nearby hospitals in the very early morning. Any shortage in production has an immediate and direct effect on users. As a result, reliability and predictability of production are extremely important for users as well as suppliers of this isotope.
The two main methods of producing F-18 use an 18O(p,n)18F reaction in a cyclotron. Both gaseous oxygen and liquid water enriched with 18O (hereinafter, O-18) have been used as target materials. However, the gaseous approach is very difficult in practice because the F-18 is very reactive and hard to recover from a gaseous medium. The overwhelming majority of production facilities use water enriched with O-18(H2[18O], hereinafter, O-18 water).
Using O-18 water is not without problems, also. For production efficiency, it is desirable to use water that is as much enriched as possible. However, 95% enriched O-18 water costs approximately $150 per ml. Also, PET has been gaining greater acceptance and the building of new O-18 water production facilities is lagging behind demand. The cost pressures make conservation and reuse of the O-18 water target material even more important.
In a typical system for F-18 production, the target is typically loaded with a pre-determined amount of O-18 water by means of a syringe or pump. The volume of water in the target is about 0.8 ml, but another 1-2 ml is required to fill the lines leading to the target. The water delivery system is then isolated from the target by means of a valve and the target is irradiated. This can be described as a xe2x80x9cstaticxe2x80x9d target, meaning that the target material remains in the target throughout the irradiation time.
The irradiated water is then removed from the target, typically by means of inert gas pressure, and transported over a delivery line leading outside the cyclotron shielding to a collection vial about 25 feet (8 m) from the target. The F-18 isotope is then separated from the water and processed for production of a radiopharmaceutical agent.
A considerable amount of O-18, typically 25-30%, is lost after each run. The O-18 isotope is used up in three ways. First, a very small amount, on the order of nanoliters, is actually converted to F-18. The next most important loss of O-18 is due to a combination of leakage and isotopic exchange with 16O oxides in the target, transport lines and storage vessels. After one run of an hour or two, the enrichment factor can drop from 95% to 85-90%. This is still high enough to be economical to run a cyclotron, but the amount of contamination is too high, as will be explained below. (As the enrichment factor falls, the irradiation time increases. 80% is a minimum under current economic conditions.)
The third loss is due to leakage of target material from the pressurized target and attached tubing which may lead to a reduced water level in the target and, if severe enough, to a catastrophic failure. Target cooling relies on the liquid water material present in the target to function as a heat conductor. A typical 1 ml target must dissipate over 500 W of heat for as long as 2-3 hours. Many target systems are pressurized to as high as 500 psig or higher to improve target thermal stability. In these conditions, containment of a small amount of water becomes a significant technical problem. Loss of a very small amount of target material may have dramatic consequences such as target foil rupture, target body degradation, and loss of target yield.
Although 70-75% of the initial O-18 water remains, the biggest effective loss is due to contamination. Any contamination in the liquid water increases the formation of super-heated steam with increased leakage and loss of cooling. Because the consequences are so adverse, the water recovered after only one run in a static target system must be sent back to the supplier for reprocessing to remove contaminants.
Existing static target systems do not provide any mechanism to timely detect the critical loss of target material during irradiation. In addition, in a static target it is impossible to monitor the amount of radioactive F-18 being produced with any certainty. The result of a production run may not be known until after its completion, up to several hours after start of production. Given the fact that production and delivery schedules do not allow much flexibility due to the extremely short half-life of the F-18, this uncertainty results in a decrease in reliability and availability of the product.
Accordingly, one objective of the invention is to increase the reliability of the production of F-18 from O-18 enriched water irradiated by high energy protons produced by a cyclotron. Further objectives are to increase the efficiency so that the cyclotron can be irradiating O-18 without interruption. Still another objective is to continually reuse O-18 water from which F-18 is periodically extracted. Another objective is to be able add additional new O-18 water as it is lost due to system leakage and the like so that the system can run for an extended period without interruption.
These objectives and more are realized with a process that continuously recirculates O-18 enriched water through a target loop that includes a target cavity for a cyclotron that irradiates the target cavity with protons to convert a portion of O-18 to F-18.
Longer irradiation without failure is achieved by using a combination of one or more of the following: maintaining a pressure of at least about 250 psig in the target cavity; recirculating the O-18 water through the target cavity at least about once every two minutes; and maintaining an O-18 water volume in the target loop that is at least about ten times the volume of the target cavity, itself. Additional benefit can be obtained by substantially cooling the O-18 water after exiting the target cavity and before reintroduction.
Increased efficiency is obtained by periodically recharging the target loop with additional O-18 water without interrupting irradiation and using protons having an energy of about 16 Mev and an intensity of at least about 40 xcexcA on the target cavity.
Rather than stop irradiation and loose cyclotron time, F-18 can be extracted from irradiated O-18 water in the target loop by periodically, e.g., every hour or two, briefly diverting the target loop through an F-18 extraction device without interrupting irradiation of the target cavity.
Because the amount of O-18 that is converted to F-18 is quite small, e.g., less than 0.1% of the O-18 is converted, after F-18 is extracted, the remaining O-18 water can be purified by solid phase purification devices and reintroduced into the target loop.
The aforementioned target loop can be implemented with, in order: an O-18 water reservoir; a pump; a target cavity; and a pressure regulator. The pump must be capable of generating the minimum desirable pressures of 250 psig and, for a typical target loop volume of 10 ml, a flow rate of 2 ml/min. Cooling of the O-18 water may be accomplished with a coil of tubing connected on the output side of the target cavity.
The F-18 may be recovered from some types of F-18 extraction devices with an eluant and a gas source for forcing the F-18 eluate into a delivery vial.
O-18 water purification devices are preferably connected through a valve to the output of the F-18 extraction device and may reintroduce O-18 water into the target loop by means of a simple check valve.
Production efficiency can be further increased by having a source vial with new O-18 water to periodically, without stopping irradiation, recharge the target loop as O-18 water is used up due to leakage and the like.
Valves and tubes are provided to controllably connect various elements to perform various functions to carry out the invention.